{"doi":"10.1016/j.molmet.2025.102159","title":"14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation","abstract":"OBJECTIVE: We previously established the scaffold protein 14-3-3ζ as a critical regulator of adipogenesis and adiposity, but whether 14-3-3ζ exerted its regulatory functions in mature adipocytes or in adipose progenitor cells (APCs) remained unclear. METHODS: To decipher which cell type accounted for 14-3-3ζ-regulated adiposity, adipocyte- (Adipoq14-3-3ζKO) and APC-specific (Pdgfra14-3-3ζKO) 14-3-3ζ knockout mice were generated. To further understand how 14-3-3ζ regulates adipogenesis, Tandem Affinity Purification (TAP)-tagged 14-3-3ζ-expressing 3T3-L1 preadipocytes (TAP-3T3-L1) were generated with CRISPR-Cas9, and affinity proteomics was used to examine how the nuclear 14-3-3ζ interactome changes during the initial stages of adipogenesis. ATAC-seq was used to determine how 14-3-3ζ depletion modulates chromatin accessibility during differentiation. RESULTS: We show a pivotal role for 14-3-3ζ in APC differentiation, whereby male and female Pdgfra14-3-3ζKO mice displayed impaired or potentiated weight gain, respectively, as well as fat mass. Proteomics revealed that regulators of chromatin remodeling, like DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1), were significantly enriched in the nuclear 14-3-3ζ interactome and their activities were impacted upon 14-3-3ζ depletion. Enhancing DNMT activity with S-Adenosyl methionine rescued the differentiation of 14-3-3ζ-depleted 3T3-L1 cells. ATAC-seq revealed that 14-3-3ζ depletion impacted the accessibility of up to 1,244 chromatin regions corresponding in part to adipogenic genes, promoters, and enhancers during the initial stages of adipogenesis. Finally, 14-3-3ζ-regulated chromatin accessibility correlated with the expression of key adipogenic genes. CONCLUSION: Our study establishes 14-3-3ζ as a crucial epigenetic regulator of adipogenesis and highlights the usefulness of deciphering the nuclear 14-3-3ζ interactome to identify novel pro-adipogenic factors and pathways.","journal":"Molecular Metabolism","year":2025,"id":539342,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9641,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1161633,"name":"Zhipeng You","orcid":"0000-0001-8779-5712","position":1,"is_corresponding":false},{"id":828580,"name":"Alexis Vivoli","orcid":"0000-0002-6056-9632","position":2,"is_corresponding":false},{"id":1426844,"name":"Fédéric Paré","orcid":null,"position":3,"is_corresponding":false},{"id":1336032,"name":"Daphné Sean","orcid":null,"position":4,"is_corresponding":false},{"id":1336033,"name":"A. Alkhoury","orcid":null,"position":5,"is_corresponding":false},{"id":234686,"name":"Geneviève Lavoie","orcid":null,"position":6,"is_corresponding":false},{"id":236714,"name":"Mete Civelek","orcid":"0000-0002-8141-0284","position":7,"is_corresponding":false},{"id":350914,"name":"Aida Martínez-Sánchez","orcid":"0000-0001-5142-2527","position":8,"is_corresponding":false},{"id":233594,"name":"Philippe P. Roux","orcid":"0000-0002-5962-0250","position":9,"is_corresponding":false},{"id":696324,"name":"Thomas M. Durcan","orcid":"0000-0003-3942-1956","position":10,"is_corresponding":false},{"id":889405,"name":"Gareth E. Lim","orcid":"0000-0003-3850-3757","position":11,"is_corresponding":false},{"id":1426843,"name":"S. Rial","orcid":null,"position":0,"is_corresponding":true}],"reference_count":107,"raw_metadata":null,"created_at":"2026-07-19T02:52:30.048313Z","pmid":"40306359","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}